Grabowski Patricia, Sturm Isrid, Schelwies Katharina, Maaser Kerstin, Buhr Heinz-Johannes, Dörken Bernd, Zeitz Martin, Daniel Peter T, Scherübl Hans
Medizinische Klinik I, Gastroenterologie/Infektiologie/Rheumatologie, Charité-Campus Benjamin Franklin, Berlin, Germany.
Int J Colorectal Dis. 2006 Apr;21(3):221-30. doi: 10.1007/s00384-005-0779-5. Epub 2005 Jun 14.
Neuroendocrine differentiation is an independent prognostic factor in colorectal cancer. Moreover, an altered p53/BAX pathway is associated with a poor clinical outcome in Union Internationale Contre le Cancer (UICC) stage III disease. Because these markers are involved in different genetic events disrupted in colorectal cancer, we investigated the prognostic power of a multimarker analysis.
Specimens were analyzed from 59 patients with UICC stage III disease who underwent surgery for colorectal adenocarcinoma at our institution and were followed up for 5 years or until death. Tumors were studied for both p53 mutation and BAX protein expression as well as for the expression of neuroendocrine markers. Statistical analysis of each marker alone or in combination was performed.
p53 status/BAX expression and neuroendocrine differentiation are not correlated in stage III colorectal cancers. However, the combination of both independent events identified a subgroup of patients with an excellent prognosis: Patients whose tumors were neuroendocrine marker-negative and who exhibited an intact p53/BAX pathway lived longer (mean survival, 93 months; range, 82-104 months) than patients whose tumors were either neuroendocrine marker-positive or whose tumors had a completely disrupted apoptotic pathway (41 months; range, 26-57 months; p<0.00001). In multivariate regression analysis, neuroendocrine marker-positive, p53 mutated, low-BAX-expressing tumors revealed an almost fivefold higher risk for earlier death (p<0.0001).
Disruption of the p53/BAX pathway is not pathognomonic for colorectal cancers with neuroendocrine differentiation. Both represent independent prognostic markers in UICC stage III disease. Therefore, the combined analysis of p53 status, BAX expression and neuroendocrine differentiation allows one to identify subgroups of patients with either very good or very poor prognosis.
神经内分泌分化是结直肠癌的一个独立预后因素。此外，p53/BAX通路改变与国际抗癌联盟（UICC）III期疾病的不良临床结局相关。由于这些标志物参与了结直肠癌中不同的基因事件破坏过程，我们研究了多标志物分析的预后价值。
对在我们机构接受结直肠腺癌手术的59例UICC III期疾病患者的标本进行分析，并随访5年或直至死亡。研究肿瘤的p53突变、BAX蛋白表达以及神经内分泌标志物的表达。对每个标志物单独或联合进行统计分析。
III期结直肠癌中p53状态/BAX表达与神经内分泌分化不相关。然而，这两个独立事件的联合确定了一个预后极佳的患者亚组：肿瘤神经内分泌标志物阴性且p53/BAX通路完整的患者比肿瘤神经内分泌标志物阳性或凋亡通路完全破坏的患者活得更长（平均生存期93个月；范围82 - 104个月）（41个月；范围26 - 57个月；p<0.00001）。在多变量回归分析中，神经内分泌标志物阳性、p53突变、低BAX表达的肿瘤显示早期死亡风险几乎高出五倍（p<0.0001）。
p53/BAX通路的破坏并非神经内分泌分化型结直肠癌的特征性表现。两者均为UICC III期疾病的独立预后标志物。因此，对p53状态、BAX表达和神经内分泌分化进行联合分析能够识别出预后非常好或非常差的患者亚组。
